Effects of Aerobic Exercise on Cardiopulmonary Function in Postoperative Patients with Congenital Heart Disease: A Meta-analysis

Background: This meta-analysis aimed to evaluate the impact of aerobic exercise on Peak VO2 (Oxygen Consumption) in postoperative patients with congenital heart disease (CHD). Besides this, we also tried to discover whether the improvement was influenced by patient ages, modes of supervision, types of exercise, the total dose of exercise, intervention periods, and types of CHD. Methods: Following the Population Intervention Comparison Outcome Study Design (PICOS) principle, a comprehensive search of the PubMed, Web of Science, Embase and Cochrane Library databases was conducted for randomized controlled trials (RCTs) evaluating the intervention effects of aerobic exercise on cardiopulmonary function in postoperative CHD patients until December 2023. This meta-analysis and publication bias tests were conducted using Stata 17.0, and the mean differences (MDs) with 95% confidence intervals (CIs) were used as effect sizes in statistics. Results: A total of 15 RCTs (762 cases) were included in this meta-analysis, with 407 cases in the experimental group and 355 cases in the control group. Meta-analysis showed that aerobic exercise had a positive effect on Peak VO2 in postoperative CHD patients (MD = 2.14, 95% CI (1.34, 2.94), p < 0.00001, I2 = 36%). The analysis of subgroups showed that intervention effects of aerobic exercise were superior to the control group when patients were >18 years old (MD = 2.53, p < 0.00001), ≤18 years old (MD = 1.63, p = 0.01), under supervision (MD = 2.23, p < 0.00001), unsupervised (MD = 2.06, p < 0.00400), performing aerobic exercise (MD = 1.87, p = 0.0003), performing aerobic exercise combined with resistance training (MD = 2.57, p < 0.00010), with a total dose of exercise ≥1440 minutes (MD = 2.45, p < 0.00010), with the intervention period of 10–12 weeks (MD = 2.31, p < 0.00001), with that >12 weeks (MD = 1.97, p = 0.00300), or with mixed types of CHD (MD = 2.34, p < 0.00001). Conclusions: This meta-analysis did not deduct points for limitations, inconsistency, indirectness, imprecision, or publication bias, so the quality of evidence was graded as high. Aerobic exercise has a significantly positive impact on improving Peak VO2 in postoperative CHD patients. Moreover, it was found that for patients aged 18 and above, supervised aerobic exercise combined with resistance training, implemented for 10–12 weeks with a total dose of exercise ≥1440 minutes, had a better intervention effect on Peak VO2. This finding provided evidence-based medicine for the exercise rehabilitation of postoperative CHD patients, and explored the optimal exercise prescription for clinical practice as well. Clinical Trial registration: Registered on INPLASY No.202440016 (https://inplasy.com).


Introduction
Congenital heart disease (CHD), caused by abnormal fetal cardiovascular development, is one of the most common congenital abnormalities [1].According to 2020 European Society of Cardiology (ESC) Guidelines for the Management of Adult Congenital Heart Disease issued by Association for European Paediatric and Congenital Cardiology (AEPC) and International Society for Adult Congenital Heart Disease (ISACHD), approximately 9 out of every 1000 newborns worldwide are affected by CHD [2].Being a condition present at birth, CHD leads to impaired blood supply to tissues and organs of the body, resulting in tissue hypoxia, which greatly hampers the growth and development of affected children.Moreover, hemodynamic abnormalities will exacerbate cardiac workload, predisposing patients to malignant arrhythmias and sudden cardiac death [3].With substantial advancements in cardiac surgery and perioperative management techniques, approximately [1] 90% of CHD patients can survive to adolescence and adulthood through surgical intervention.Nevertheless, postoperative patients with CHD often encounter long-term issues such as hypoxia and reduced exercise endurance [4,5].These challenges directly impact patients' oxygen supply capacity and exercise endurance, posing an urgent need for effective strategies to enhance postoperative cardiopulmonary function of CHD patients.
In the United States and Europe, the guidelines for CHD patients suggest that moderate and sustained aerobic exercise will enhance the contraction and relaxation abilities of the myocardium, promote blood circulation, increase coronary blood flow, and elevate functional capacity of the heart [6,7].Studies have found a range of positive ef-fects during aerobic exercise, such as increased respiratory rate and depth, expanded lung capacity, and improved endurance, all of which can enhance the function of postoperative CHD patients, thereby improving their quality of life [8][9][10].
Cardiopulmonary Exercise Test (CPET) serves as a cornerstone for health evaluation and exercise prescription, and is deemed as the "gold standard" for diagnosing CHD patients' cardiopulmonary functions [11].Relevant indicators such as the cardiorespiratory reserve function and exercise endurance of CHD patients can be assessed by CPET.Peak oxygen consumption (VO 2 ) represents the oxygen uptake when CHD patients reach their maximum exercise load during CPET, reflecting the body's maximal aerobic metabolism and cardiorespiratory reserve capacity.As a result, it is the optimal indicator for assessing aerobic metabolic capacity.The prognostic significance of Peak VO 2 for mortality and morbidity rates in CHD patients has been proven [12][13][14][15].Multiple studies have shown that there is an inverse relationship between Peak VO 2 and the risk of cardiovascular events, and a direct correlation between Peak VO 2 and cardiopulmonary functions in CHD patients [11,16,17].Laukkanen et al. (2016) [18] demonstrated through their studies that for every increase of 1 mL/kg/min in Peak VO 2 , there is a 9% reduction in relative risk of all-cause mortality (hazard ratio = 0.91; 95% CI, 0.87-0.95),emphasizing the importance of maintaining good cardiopulmonary function.Study results from Opotowsky et al. (2018) [19][20][21][22][23][24][25][26][27][28][29] indicated that aerobic exercise can increase Peak VO 2 in postoperative CHD patients.An RCT by Westhoff-Bleck et al. (2013) [26] showed that exercise for 24 weeks at a heart rate of 110.3 ± 9.7 beats per minute resulted in an increase in Peak VO 2 (1.8 ± 2.3 mL/kg/min; +7.7%).Winter et al. (2012) [27] found significant changes in Peak VO 2 after 10 weeks of aerobic exercise.
A review of prior research reveals inconsistent findings regarding the effect of aerobic exercise on Peak VO 2 in postoperative CHD patients.The meta-analysis results by Xu C et al. (2020) [30] indicated that exercise has no significant impact on Peak VO 2 , a conclusion also reached by Klausen et al. (2016) [31].However, studies by Opotowsky et al. (2018) [19][20][21][22][23][24][25][26][27][28][29] suggested that aerobic exercise provides substantial benefits for Peak VO 2 in postoperative CHD patients.The disparities in these findings may be due to the small sample sizes in each experiment and remarkable age differences among participants in these studies.Furthermore, we also found that previous studies have not clarified whether different exercise elements have an effect on Peak VO 2 in postoperative CHD patients.Thus, this study, harnessing the methodology of evidencebased medicine, aims to systematically evaluate and analyze whether aerobic exercise can effectively improve Peak VO 2 in CHD patients.We also tried to figure out whether the effectiveness is influenced by factors such as patient age, modes of supervision, types of exercise, and the types of CHD.Moreover, this study observed whether the duration, frequency, and intervention period of aerobic exercise present a dose-response effect for improving CHD patients' condition.In conclusion, this study aims to identify the potential dose-response effect of aerobic exercise on Peak VO 2 in postoperative CHD patients, ascertain the optimal exercise regimen for enhancing Peak VO 2 in postoperative CHD patients, and provide evidence-based clinical support.

Materials and Methods
Regarding the selection and utilization of research methods, this study adhered to the PRISMA writing guidelines for meta-analysis [32], and has been registered on IN-PLASY No.202440016 (https://inplasy.com).

The Research Framework
The research framework is based on 2020 ESC Guidelines for the management of adult congenital heart disease [2] issued by AEPC and ISACHD.It involves an analysis of patient information including age, modes of supervision, types of exercise, the dose of exercise, intervention periods, and types of CHD.This study aims to analyze the intervention effects of exercise on the cardiorespiratory function and exercise endurance of postoperative CHD patients by observing the changes in Peak VO 2 .Additionally, we aim to investigate potential dose-effects of aerobic exercise on the optimal intervention period, the dose of exercise, types of exercise, and modes of supervision for postoperative CHD patients.The Population Intervention Comparison Outcome Study Design (PICOS) framework for this systematic review is presented in Table 1.OR "resistance exercise"[Title/Abstract] AND "Cardiorespiratory function"[Mesh] OR "exercise endurance"[Title/Abstract] OR "peak oxygen uptake"[Title/Abstract] AND "randomized controlled trial"[Publication Type] (Take PubMed as an example).

Inclusion and Exclusion Criteria 2.3.1 Inclusion Criteria
(1) The subjects included in study were diagnosed as postoperative CHD patients by the hospital.( 2) The experimental group took aerobic exercise as an intervention in addition to routine postoperative care, with the intervention period being ≥10 weeks.(3) The control group skipped exercise interventions and only adopted routine postoperative care.(4) The primary outcome was Peak VO 2 .(5) All included studies were RCTs.

Exclusion Criteria
(1) Patients with contraindications for exercise, conditions such as pregnancy or history of sudden death, and those with abnormal exercise test results.Exercise contraindications also include patients with acute illnesses such as acute heart, liver, gallbladder, pancreas, stomach, intestine, and kidney diseases, early-stage viral myocarditis, acute viral hepatitis, acute phase of pulmonary tuberculosis, etc.; patients with hemorrhagic diseases such as leukemia, hemophilia, thrombocytopenic purpura, etc.; patients with malignant tumor metastasis; and patients with coronary artery disease, etc. ( 2

Study Celection, Data Extraction, and Quality Assessment 2.4.1 Study Selection and Data Extraction
After retrieving the relevant literature, they would be further deduplicated in Endnote.Two researchers selected studies and extracted data independently in a double-blind trial.Extracted data were inputted into RevMan 5.4.1 (The Cochrane Collaboration, 11-13 Cavendish Square, London W1G 0AN, UK), and their accuracy was double-checked.In case of discrepancies, a third researcher would be consulted to decide whether to include the data.Extracted data included the first author's name, publication year, publication country, baseline information of the study subjects (age, gender, and stages of recovery), interventions and outcomes.

Quality Assessment
The methodological quality of included studies was evaluated using the Physiotherapy Evidence Database (PE-Dro) scale [33], which includes 10 items: "random allocation" "concealed allocation" "similarity at baseline" "subject blinding" "therapist blinding" "assessor blinding" ">85% follow up" "intention-to-treat analysis" "betweengroup statistical comparison" and "point and variability measures".One point was awarded for meeting a criterion, and zero points for not meeting it.The total score was 10 points, with <4 points indicating low quality, 4-5 points indicating moderate quality, 6-8 points indicating good quality, and 9-10 points indicating high quality.Only studies of moderate quality or above were included in this study.
Evidence for the quality of outcomes was evaluated using the GRADEpro evidence rating system, which categorizes evidence quality as high, moderate, low, or very low.Quality assessment was conducted by two researchers respectively, and in case of discrepancies, a third researcher would be involved in the discussion until a consensus was reached.

Data Processing
RevMan 5.4.1 software was used for heterogeneity assessment of all outcomes in the included studies.The sample sizes as well as the mean and standard difference of the improvement values before and after interventions were assessed.The included outcomes were all continuous vari-

Literature Search Results
A total of 3807 relevant pieces of literature were identified through searches in PubMed, Embase, Web of Science, and Cochrane databases.Additionally, 2 articles were manually retrieved from other sources.After removing duplicates and preliminary screening based on titles and abstracts, 66 articles were selected.Following a full-text assessment and exclusion of articles that failed to meet the eligibility, a final set of 12 articles were included, comprising 15 RCTs for our meta-analysis (Fig. 1).

Quality Assessment of Included Studies
All 12 articles included in this study employed an RCT or quasi-RCT design.Additionally, they all met the criteria of "similarity at baseline" "intention-to-treat analysis" "between-group statistical comparison" and "point and variability measures".Additionally, 11 studies employed "random allocation"; 4 studies met the criterion of "concealed allocation"; 5 studies met the criterion of "subject blinding"; 3 studies met the criterion of "therapist blinding"; 2 studies met the criterion of "assessor blinding"; and 9 studies met the criterion of ">85% follow up".The PE-Dro scores ranged from 6 to 8 points, with an average score of 6.75 points.There were no studies which scored under 5 points, indicating overall good quality of the included studies, as shown in Table 3 (Ref.[19][20][21][22][23][24][25][26][27][28][29]31]).

Heterogeneity Tests
Heterogeneity tests were conducted to examine if there was significant heterogeneity among the studies.The results showed that all studies were within the range of [-2, +2], which indicated good homogeneity and a certain level of stability and reliability among the studies.See Fig. 3.

Analyses of the Moderating Effect of Subgroups
To explore potential sources of heterogeneity, this study analyzed outcome in subgroups, as presented in Table 4 (Ref.[19][20][21][22][23][24][25][26][27][28][29]31]).The impact of aerobic exercise on Peak VO 2 [mL/kg/min] in postoperative CHD patients may be associated with factors such as age, modes of supervision, types of exercise, the total dose of exercise (frequency of exercise time, unit: minutes), intervention periods, and the types of CHD.We categorized age into two subgroups: >18 years old and ≤18 years old; modes of supervision into supervised and unsupervised subgroups; types of exercise into aerobic exercise and aerobic exercise combined with resistance training subgroups; the total dose of exercise into <1440 minutes and ≥1440 minutes subgroups; intervention periods into 10-12 weeks and >12 weeks subgroups; the types of CHD into Tetralogy of Fallot (ToF) and mixed subgroups.Age, modes of supervision, intervention periods, and the types of CHD may be sources of heterogeneity.

Sensitivity Analysis
To investigate whether the heterogeneity among studies was caused by certain studies, this study conducted a sensitivity analysis by excluding individual studies one by one to analyze the combined effect, as shown in Table 5.After excluding the study by Klausen et al. (2016) [31], the combined effect was MD = -3.4,95% CI (-6.44, -0.36), and I 2 decreased from 36% to 0%, indicating a significant reduction in heterogeneity, and the difference compared to the control group was statistically significant.Since the study by Klausen et al. (2016) [31] used unsupervised intervention for 52 weeks, modes of supervision and intervention periods may be sources of heterogeneity.After excluding Klausen's study, the combined effect size MD and I 2 all remained stable, with p < 0.00001, suggesting robust results, indicating that compared to the control group, aerobic exercise effectively enhanced Peak VO 2 in postoperative CHD patients.

Publication Bias
The funnel plot of the intervention effects of aerobic exercise on Peak VO 2 in postoperative CHD patients shows symmetrical distribution.Egger's Test yielded a result of t = -0.64,p > |t| = 0.5338, indicating no publication bias in the studies, as shown in Fig. 4.

Quality of Evidence Assessment
According to GRADEPro, there were no deductions in terms of limitations, inconsistency, indirectness, imprecision, and publication bias of this study.Therefore, the quality of evidence was graded as high (Table 6).The above results suggested that the intervention effects of aerobic exercise on Peak VO 2 in postoperative CHD patients is likely close to reality.
Therrien et al.
Fredriksen et al.

Adverse Events
In the study by Sandberg et al. 2018 [20], one participant experienced discomfort and arrhythmia during exercise training, leading to the cessation of exercise.However, no arrhythmia was observed in subsequent exercise tests and dynamic electrocardiograms.Apart from this event, no other exercise-related adverse events occurred.

Discussion
The results of this study showed that aerobic exercise can improve Peak VO 2 in postoperative CHD patients.A MD of 2.14 in Peak VO 2 was observed.This change indicated that even a slight increase in Peak VO 2 may signify a significant improvement in cardiopulmonary function and exercise capacity in CHD patients [21].Therefore, the increase of Peak VO 2 not only provides clinicians with a valuable indicator for assessing patient prognosis but also offers valuable guidance for developing personalized treatment plans and exercise prescriptions.The meta-analysis results of Li et al. 2019 [34] also supported this conclusion (MD = 1.96).Additionally, the result validated the study by Gomes-Neto et al. 2016 [34,35], indicating the effectiveness of aerobic exercise intervention on Peak VO 2 in child, adolescent, or adult postoperative CHD patients.Meyer et al. 2020 [36] suggested that unsupervised home-based aerobic exercise can improve Peak VO 2 in postoperative CHD patients, aligning with the results of this study.Although the mechanism by which exercise increases Peak VO 2 remains unclear, exercise has been proven to improve peripheral muscle function [37], enhance autonomic nervous system regulation, increase vagal activity, inhibit sympathetic activation, and reduce levels of angiotensin and renin, thereby improving cardiopulmonary function [34].
Our study included a total of 15 RCTs (762 patients) for a systematic review and analysis of the intervention effects of aerobic exercise on Peak VO 2 in postoperative CHD patients.Included studies were quality-assessed by the PEDro scale, with an average score of 6.75 points.There were no low-quality studies found, indicating satisfactory quality of the overall included studies.There appeared to be no noticeable publication bias.I 2 = 36%, after subgroup analysis, it was found that the patients' age, modes of supervision, types of exercise, the total dose of exercise, intervention periods, and types of CHD might be sources of heterogeneity; sensitivity analysis revealed that intervention periods and modes of supervision could be sources of heterogeneity.The quality of evidence evaluation had no deductions for limitations, inconsistency, indirectness, imprecision and publication bias.Overall, the intervention effects of aerobic exercise on Peak VO 2 in postoperative CHD patients were classified under high quality evidence.In addition, this study has certain limitations.There was certain heterogeneity among exercises with different types, frequencies, intensities, durations, and periods, which may affect the overall effect size and subgroup analyses.Besides, it was difficult to implement complete blinding in exercise interventions, and there was diversity in the patients' conditions and stages of recovery.
In this study, it was found that for adult patients aged 18 and above, supervised aerobic exercise combined with resistance training, implemented for 10-12 weeks with a total dose of exercise ≥1440 minutes, helps to significantly improve Peak VO 2 .This may be attributed to the differing cardiovascular responses between adults and children.The smaller size of children's hearts results in lower venous return and consequently lower cardiac output, leading to a lower Peak VO 2 compared with adults, thereby resulting in less significant variations in Peak VO 2 [38].The intervention period of 10-12 weeks with a minimum exercise dosage of 1440 minutes yielded the best outcomes, possibly due to the more pronounced immediate effects of aerobic exercise.Besides, with the increase of total treatment duration within the same intervention period, the increased treatment volume reaches a threshold that beneficially impacted cardiopulmonary function.Regarding the mode of supervision, on-site supervision by trainers proved most effective, followed by unsupervised home-based exercise accompanied with consultation, encouragement, and electronic applications, which also contributed to the rehabilitation of cardiopulmonary function in patients.There is research indicating that home-based exercise interventions are safe and feasible, representing an effective alternative to supervised cardiac rehabilitation [36].Aerobic exercise combined with resistance training can slightly improve cardiopulmonary health by mechanisms such as increasing muscle strength, thus improving oxidative enzymes and increasing type II muscle fibers [39].
The results of this study also demonstrated that there was no significant difference in intervention effects of aerobic exercise on the ToF subgroup.Williams et al. (2020) [40], in their meta-analysis, arrived at the same conclusion.However, among included studies, results of 4 RCTs by Ávila et al. (2016) [22,23,28,29] all indicated a significant intervention effect of aerobic exercise on Peak VO 2 in postoperative ToF patients, with only Novaković et al. (2018) [29] expressing disagreement.The reason for the non-significant intervention effect of aerobic exercise on the ToF subgroup in this study may be attributed to insufficient sample size, necessitating further high-quality RCTs for clarification.

Conclusions
In summary, aerobic exercise could significantly improve Peak VO 2 in postoperative CHD patients.For pa-tients aged 18 and above, a 10-12 weeks supervised intervention integrating aerobic exercise with resistance training, with a total exercise dosage of at least 1440 minutes, yielded better results.Current evidence of included studies suggests that aerobic exercise is significant and safe for enhancing Peak VO 2 in postoperative CHD patients.Despite certain limitations, our study provided evidence-based medicine for the exercise rehabilitation of postoperative CHD patients.Finally, we look forward to further research in this area to explore the intervention effects and mechanisms of exercise on postoperative CHD patients with different conditions and at different stages of recovery.
Two retrieval personnel searched PubMed, Embase, Web of Science, and Cochrane databases respectively to collect randomized controlled trials (RCTs) about the effects of aerobic exercise on cardiopulmonary function and exercise endurance in postoperative CHD patients.The retrieval period extended from the establishment of each database to December 31, 2023.Additionally, manual searches of previously written reviews were conducted, included in relevant literature to acquire full-text articles.The literature was searched using the following words "Heart Defects, Congenital"[Mesh] OR "congenital heart disease"[Title/Abstract] OR "atrial septal defect"[Title/Abstract] OR "ventricular septal defect"[Title/Abstract] OR "cardiac function"[Title/Abstract] OR "pulmonary hypertension"[Title/Abstract] AND "Exercise"[Mesh] OR "motion"[Title/Abstract] OR "movement"[Title/Abstract] OR "sport"[Title/Abstract] OR "physical activity"[Title/Abstract] OR "rehabilitation training"[Title/Abstract] OR "high intensity interval training"[Title/Abstract] OR "moderate intensity exercise"[Title/Abstract] OR "aerobic training"[Title/Abstract] ) Duplicated publications.(3) Unclear experimental data descriptions, inconsistent baselines, lack of pre-test data, and no response from authors, making it impossible to calculate or extract data.(4) Inappropriate interventions or mismatched outcomes.

Table 1 . PICOS framework for intervention effects of exercise on cardiorespiratory function and exercise endurance in CHD patients.
Study design Randomized controlled trials CHD, congenital heart disease; PICOS, Population Intervention Comparison Outcome Study Design; VO 2 , oxygen consumption.

Table 2 . Basic characteristics of included studies.
Aerobic exercise combined with resistance training; z Routine care; THR, training heart rate; HRmax, maximum heart rate; RHR, resting heart rate; VO 2 , oxygen consumption.ables.For outcomes with the same measurement method and unit, mean difference (MD) was used, and for those with different measurement methods or units, the standard mean difference (SMD) was used.We used a threshold of p less than 0.05 and I 2 greater than 50% to represent heterogeneity for studies, and a random-effects model would be employed.Conversely, if there was no significant heterogeneity among studies (p ≥ 0.05 or I 2 ≤ 50%), a fixedeffects model would be used.Through subgroup analysis, we divided the study sample into different subgroups based on specific variables (such as age, gender, stage of recovery., etc.) and conducted independent statistical analyses for each subgroup to explore and explain the differences in results among different subgroups.This helps to reveal the heterogeneity of the study results, indicating that different subgroups may respond differently to interventions or exposure factors.The process of subgroup analysis included: defining subgroups (the classifications were based on previous research literature), data segmentation, independent analysis, result comparison, and result interpretation.Sensitivity analysis involved changing key assumptions or methods during the analysis process and reanalyzing the data to test whether the original results are influenced by specific analysis choices and to evaluate the robustness of the study results.The process of sensitivity Notes: T, treatment group; C, control group; Y, yes; N, no; Intervention, x Aerobic exercise; y analysis included: identifying key assumptions, changing assumptions, re-analyzing, comparing results, and validating conclusions.The outcomes of our meta-analysis were presented with a 95% CI.Publication bias and heterogeneity tests were conducted using Stata 17.0 (StataCorp, College Station, TX, USA).

Table 6 . Quality of evidence assessment by GRADE.
Grading of Recommendations, Assessment, Development and Evaluation; VO 2 , oxygen consumption.